The present invention relates to methods for the treatment of conditions related to Mycobacterium tuberculosis infection. The invention also relates to compounds and compositions useful in the treatment of Mycobacterium tuberculosis infection. The invention further relates to a method useful in the stepwise reductive amination of ketones.
Infectious diseases remain the largest cause of death in the world today, greater than cardiovascular disease or cancer1. Tuberculosis (TB), caused by Mycobacterium tuberculosis, a facultative intracellular bacillus, is the world""s number one killer among the infectious diseases and the leading cause of death among women of reproductive age2. Even though the improved methods of prevention, detection, diagnosis, and treatment have greatly reduced the number of people who contract the disease and die from it, the emergence of multidrug-resistant (MDR) strains3 and the global human immunodeficiency virus (HIV) pandemic have amplified the incidence of TB.
It has been estimated one-third (about 2 billion) of the world""s population, including 15 million Americans, is infected with M. tuberculosis4. The lifetime risk of developing TB is approximately 10% of infected persons, while the remaining 90% have latent infection with viable bacilli. This 10% rate of TB accounts for the 8 million cases of each year, resulting in 3 million deaths. The gravity of the situation led the World Health Organization (WHO) in 1993 to declare TB a global emergency in an attempt to heighten public and political awareness.
HIV is the most powerful factor known to increase the risk of TB. At first, HIV increases a person""s susceptibility to infection with M. tuberculosis. In 1995, about one third of the 17 million HIV-infected people worldwide were also co-infected with M. tuberculosis5. As HIV infection progresses, CD4+ lymphocytes decline in number and function and, therefore, the immune system is less able to prevent the growth and local spread of M. tuberculosis, rendering a rapid progression of TB infection to disease. An individual co-infected with HIV and M. tuberculosis has a 10 times greater risk of developing TB, compared to an individual who is not infected with HIV. On the other hand, TB infection in an HIV-infected person may allow HIV to multiply more quickly and lead to a more rapid disease progression of AIDS5.
The recommended treatment of TB is Directly Observed Therapy Short-course (DOTS), which uses a combination of drugs with isoniazid and rifampin taken over 6 months, supplemented with pyrazinamide for the first 2 months, and addition of ethambutol when isoniazid resistance is suspected. DOTS is generally successful, even though the treatment may need to be extended, sometimes to as long as 2 years, in order to fully cure the patient of infectious bacteria. However, poor compliance with such a long, complex and unpleasant combination of drugs results in a significant treatment failure rate. Worse still, resistance may emerge to these first-line agents, and thereafter to a wide range of second-line anti-mycobacterials. Not only are multi-drug resistant-TB (MDR-TB) strains difficult to treat but these strains are also life threatening, sometimes resulting in a high mortality rate (e.g., 72 to 89%) in a short period of time (e.g., 4 to 6 weeks)6. In general, treating individuals infected with MDR-TB is expensive, intolerable in toxicity, and frequently unsuccessful. Treatment of drug susceptible TB costs about $2,000 per patient, whereas the cost increases to as much as $250,000 per case for MDR-TB7. In late 1998, FDA approved a new drug rifapentine, a derivative of rifampin, the first anti-TB drug to be approved in 25 years8. Although TB relapse rate for rifapentine is slightly higher (10%) than that for rifampin (5%), FDA approved the new medication because it only has to be taken once weekly during the last four months of treatment, as opposed to twice weekly for rifampin.
Currently, there is no standard optimal antimicrobial therapy in AIDS patients and no single agent that is active against both infections. Challenges of management of TB in patients with AIDS are significantly higher than that in patients without AIDS. The first challenge is the pill burden. DOTS program for TB requires a patient to take 10 to 12 pills a day and the recommended highly active antiretroviral therapy (HAART) for HIV infection normally adds no less than another 20 pills. All the medications have to be taken daily, around the clock, with or without food restrictions, creating a tremendously difficult drug regimen for the patient. The second challenge is the interactions between the drugs for TB and HIV infections, which may lead to regimen intolerance and/or contraindication and add more difficulties in the treatment design. For example, rifampin is not recommended for concurrent use with almost all the anti-HIV NNRTIs and protease inhibitors, due to their contraindicated interactions.
It is clear that there is an urgent need for anti-TB drugs with improved properties such as enhanced activity against MDR strains, reduced toxicity, shortened duration of therapy, rapid mycobactericidal mechanism of action, ability to penetrate host cells and exert antimycobacterial effect in the intracellular environment.
It is an object of this invention to provide for the design, synthesis and evaluation of a library of pyranocoumarin analogues, with an ultimate goal of developing a novel anti-TB drug which should maintain the same unique resistance profile and unique mechanism of action as demonstrated by (+)-calanolide A but have improved potency.
It is another objective of this invention to further understand the structural features of pyranocoumarin necessary for the unique anti-TB activity. The compounds of the present invention are useful tool to study a structure-activity relationship (SAR), to select and/or design other molecules to inhibit and/or kill M. tuberculosis. In addition, the instant compounds of the present invention are useful tools and/or reagents to identify and validate novel targets in the life cycle of M. tuberculosis for anti-TB drug development. Furthermore, the instant compounds of the present invention can be used to probe the mechanism of actions for anti-TB agents.
The present invention provides for compounds according to formula I, compositions comprising the compounds of formula I, and methods for treating a patient who has a condition or disease associated with Mycobacterium infection and who is in need of such treatment which comprises administration of a therapeutically effective amount of at least one compound of formula I: 
wherein
R1 is alkyl, alkenyl, alkynyl, aryl, OH, or NH2;
R2 is selected from H, alkyl, alkenyl, alkynyl, aryl, and can optionally form a 4 to 7-membered ring with R3;
R3 is selected from H, alkyl, alkenyl, alkynyl, aryl, and can optionally form a 4 to 7-membered ring with R2;
R4 is selected from H, alkyl, alkenyl, alkynyl, aryl, and can optionally form a 4 to 7-membered ring with R5;
R5 is selected from H, alkyl, alkenyl, alkynyl, aryl, and can optionally form a 4 to 7-membered ring with R4; and
R6 is selected from the group consisting of xe2x95x90O, OH, xe2x95x90NH, NH2, SH, P(O)nHm substituted imines, and substituted amines, wherein n is 2-4 and m is 1-3;
The invention also provides a method for the reductive amination of a ketone comprising contacting the ketone with a compound of the formula Rxe2x80x2NH2, wherein Rxe2x80x2 is selected from the group consisting of H, alkyl, alkenyl, alkynyl, and aryl.